Abstract: The overall goal of these studies is to investigate the mechanism(s) underlying hematopoietic stem- progenitor cells (HSPCs) mediated immune suppression during stress. Stress has dramatic impacts on the immune system and consequently contributes to the onset and progression of a variety of diseases, including immune disorders, infections, and cancer. However, the mechanisms by which stress affects the immune system remain to be elucidated. We utilize a mouse model of restraint stress, which has been widely used, including in our laboratory and others, to study the effects of stress on immune responses. Using this model we discovered that HSPCs prevent restraint stress-induced lymphocyte apoptosis. We found that nitric oxide (NO) is essential for the protective effects of HSPCs on splenocyte reduction and suppression of delayed type hypersensitivity response induced by stress. We also found that blockage of IFN? abolishes the protective effect of HSPCs on stress-induced splenocyte reduction. To the best of our knowledge, this is a new and novel role for HSPCs in the pathogenesis of stress-induced immune responses. However, the mechanisms by which HSPCs modulate stress-induced immune suppression remain to be defined. At present, we do not understand the role of HSPC-mediated NO signaling in stress- induced immune suppression, nor do we understand the effect of HSPC-mediated IFN? signaling on lymphocyte apoptosis during stress. Based on our novel findings, we hypothesize that HSPCs prevent stress-induced immune suppression by modulating NO and IFN? signaling pathways. We propose the following two aims to test this hypothesis. Aim 1 will investigate the contribution of HSPCs in NO- mediated immune suppression induced by stress. We hypothesize that HSPCs prevent stress-induced immune suppression through NO. To test this hypothesis, we will administer HSPCs, HSPCs plus iNOS inhibitor in wild type mice, HSPCs in iNOS deficient mice, and then subjected to stress for different time periods. We will determine the effect of HSPC-mediated NO signaling on lymphocyte apoptosis and immune suppression following stress. Aim 2 will define the effect of HSPCs on IFN?-mediated apoptotic signaling following stress. Our hypothesis is that HSPCs prevent stress-induced lymphocyte apoptosis in an IFN? dependent mechanism. To determine this hypothesis, we will administer HSPCs, HSPCs plus IFN? antibody in wild type mice, HSPCs in IFN?-R1 deficient mice, and then subject mice to stress for different time periods. The effect of HSPC-mediated IFN? signaling on lymphocyte apoptosis will be investigated. Our studies should delineate the mechanisms underlying HSPC-mediated signaling in immune suppression and provide novel information for the development of countermeasures against the deleterious effects of chronic stress on the immune system.